US9540356B2ActiveUtilityPatentIndex 70
Compounds having a protective activity against toxins with intracellular activity
Assignee: COMMISSARIAT ENERGIE ATOMIQUEPriority: Oct 19, 2012Filed: Oct 18, 2013Granted: Jan 10, 2017
Est. expiryOct 19, 2032(~6.3 yrs left)· nominal 20-yr term from priority
C07D 409/14C07D 417/14C07D 409/04C07D 239/91A61P 39/02
70
PatentIndex Score
2
Cited by
12
References
12
Claims
Abstract
The present invention concerns a new family of 2,3-dihydroquinazolin-4(1H)-one compounds of general formula (I), and the use thereof as inhibitors of the toxic effects of toxins with intracellular activity, such as ricin or Shiga toxin, for example, using retrograde transport to intoxicate cells.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A compound of formula (I):
wherein:
R 1 represents a hydrogen atom, a halogen atom or an alkoxy radical having from 1 to 3 carbon atoms;
R 2 represents a phenyl ring, optionally substituted with: a phenyl radical, a halogen atom, an —SO 2 -phenyl group or an —S—X or —O—X group, X being an alkyl radical having from 1 to 4 carbon atoms, an alkoxy having from 1 to 4 carbon atoms or a PEG of formula —(CH 2 —CH 2 —O) n —R with n being 1 to 10, and R is a hydrogen atom or a methyl radical, or a —CO—Y or —CO—O—Y group, Y being a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, a phenyl ring or an allyl (—CH 2 —CH═CH 2 ) group;
R 3 represents a thiophene ring substituted on C5′ of the thiophene, the quinazolinone ring being bonded to C2′ of the thiophene, with
an alkyl radical having from 1 to 3 carbon atoms;
a halogen atom;
a phenyl radical optionally substituted with an alkoxy radical having from 1 to 3 carbon atoms, a —CN group, an —NO 2 group or a —COX or —COOX group with X an alkyl radical having from 1 to 4 carbon atoms, or a combination of these substituents;
an —SY group, Y being an alkyl radical having from 1 to 4 carbon atoms or a phenyl radical;
a —CN group;
a —CH 2 —N 3 group;
an aromatic heterocycle having 5 or 6 atoms selected from the group consisting of a furan, a thiophene, a pyrrole, a pyrroline, a pyrrolidine, a dioxolane, oxazole, a thiazole, an imidazole, an imidazoline, an imidazolidine, a pyrazole, an isoxazole, an isothiazole, a pyran, a pyridine, a piperidine, a dioxane, a morpholine, a pyridazine, a pyrimidine and a pyrazine ring, optionally substituted with at least one alkyl radical having from 1 to 3 carbon atoms, a —CH 2 —N 3 , group, or both;
R 4 represents a hydrogen atom or a methyl radical; and
with the exclusion of 3-(4-chlorophenyl)-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one and of the compound such that R 1 is a hydrogen atom, R 2 a phenyl radical, R 3 a 5-methylthiophen-2-yl radical and R 4 a hydrogen atom.
2. The compound of claim 1 , which is selected from the group consisting of
Molecule
Compound
Name
RN-1-068
7
2-(5-Ethylthiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-
4(1H)-one
RN-1-100
9
2-(5-Bromothiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-
4(1H)-one
RN-1-148
13
3-Phenyl-2-(5-phenylthiophen-2-yl)-2,3-dihydroquinazolin-
4(1H)-one
RN-1-149
14
3-([1,1′-Biphenyl]-4-yl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-1-162
16
8-Methyl-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-1-173
17
2-(5-(Methylthio)thiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-1-174
18
2-([2,2′-Bithiophen]-5-yl)-3-phenyl-2,3-dihydroquinazolin-
4(1H)-one
RN-1-175
19
3-Phenyl-2-(5-(pyridin-2-yl)thiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-1-176
20
2-(5-(Furan-2-yl)thiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-1-177
21
2-(5-(2-Methylthiazol-4-yl)thiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-120
22
3-(4-Fluorophenyl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-137
23
3-(2-Fluorophenyl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-161
24
6-Methoxy-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-162
25
6-Fluoro-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-163
26
7-Fluoro-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-177
27
3-(4-Bromophenyl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-178
28
3-(3-Bromophenyl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-181
30
3-(3-Chlorophenyl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-183
31
3-(2-(Methylthio)phenyl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-182
32
3-(2-Chlorophenyl)-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-199
33
6-Iodo-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-3-121
34
6-Fluoro-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-3-phenyl-
2,3-dihydroquinazolin-4(1H)-one
RN-1-181
35
1-Methyl-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-1-186
36
1-Methyl-3-phenyl-2-(5-phenylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-1-192
37
1-Methyl-3-phenyl-2-(5-(pyridin-2-yl)thiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-1-196
38
1-Methyl-2-(5-(methylthio)thiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-1-197
39
2-([2,2′-Bithiophen]-5-yl)-1-methyl-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-001
40
2-(5-(Furan-2-yl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-005
41
2-(5-Ethylthiophen-2-yl)-1-methyl-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-015
42
1-Methyl-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-3-phenyl-
2,3-dihydroquinazolin-4(1H)-one
RN-2-016
43
2-(5-Bromothiophen-2-yl)-1-methyl-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-019
44
1-Methyl-3-phenyl-2-(5-(phenylthio)thiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-2-029
45
2-(5-(3,4-Dimethoxyphenyl)thiophen-2-yl)-1-methyl-3-phenyl-
2,3-dihydroquinazolin-4(1H)-one
RN-2-032
46
1-Methyl-2-(5-(3-nitrophenyl)thiophen-2-yl)-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-034
47
2-(5-(Furan-3-yl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-049
48
Methyl 4-(5-(1-methyl-4-oxo-3-phenyl-1,2,3,4-
tetrahydroquinazolin-2-yl)thiophen-2-yl)benzoate
RN-2-050
49
2-(5-(4-Acetylphenyl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
RN-2-053
50
1-Methyl-3-phenyl-2-(5-(3,4,5-trimethoxyphenyl)thiophen-2-
yl)-2,3-dihydroquinazolin-4(1H)-one
RN-2-057
51
1-methyl-2-(5-(4-methyl-3-nitrophenyl)thiophen-2-yl)-3-
phenyl-2,3-dihydroquinazolin-4(1H)-one
RN-2-059
52
4-(5-(1-Methyl-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-2-
yl)thiophen-2-yl)benzonitrile
RN-3-012
53
5-(1-Methyl-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-2-
yl)thiophene-2-carbonitrile
RN-3-066
54
3-(2-Chlorophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-3-067
55
3-(2-Iodophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-3-068
56
3-(2-Methoxyphenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-3-069
57
1-Methyl-3-(2-(methylthio)phenyl)-2-(5-methylthiophen-2-yl)-
2,3-dihydroquinazolin-4(1H)-one
RN-3-070
58
3-(2-Fluorophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-
dihydroquinazolin-4(1H)-one
RN-3-089
59
3-([1,1′-Biphenyl]-2-yl)-1-methyl-2-(5-methylthiophen-2-yl)-
2,3-dihydroquinazolin-4(1H)-one
RN-3-098
60
1-Methyl-2-(5-methylthiophen-2-yl)-3-(2-
(phenylsulfonyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one
RN-3-122
61
6-Fluoro-1-methyl-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-
3-phenyl-2,3-dihydroquinazolin-4(1H)-one
RN-3-061
62
2-(5-(Azidomethyl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-
dihydroquinazolin-4(1H)-one
VP37
63
2-(5-(2-(Azidomethyl)thiazol-4-yl)thiophen-2-yl)-1-methyl-3-
phenyl-2,3-dihydroquinazolin-4(1H)-one
VP153
64
2-(5-(2-(Azidomethyl)thiazol-4-yl)thiophen-2-yl)-6-fluoro-1-
methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one
VP22
65
3-(2-Benzoylphenyl)-1-methyl-2-(5-(2-methylthiazol-4-
yl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one
VP104
66
3-(2-Benzoylphenyl)-6-fluoro-1-methyl-2-(5-(2-methylthiazol-
4-yl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one
KH071-4
67
Allyl 2-(1-methyl-2-(5-methylthiophen-2-yl)-4-oxo-1,4-
dihydroquinazolin-3(2H)-yl)benzoate
KH093-4
68
3-(2-(2-Methoxyethoxy)phenyl)-1-methyl-2-(5-
methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one, and
KH112-2
69
2-(1-Methyl-2-(5-methylthiophen-2-yl)-4-oxo-1,4-
dihydroquinazolin-3(2H)-yl)benzoic acid.
3. The compound of claim 1 , wherein R 2 is a phenyl ring substituted on its carbon C2″.
4. The compound of claim 2 , which is selected from the group consisting of
3-(2-Fluorophenyl)-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-(Methylthio)phenyl)-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Chlorophenyl)-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Chlorophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Iodophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Methoxyphenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-3-(2-(methylthio)phenyl)-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Fluorophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-([1,1′-Biphenyl]-2-yl)-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-2-(5-methylthiophen-2-yl)-3-(2-(phenylsulfonyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Benzoylphenyl)-1-methyl-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Benzoylphenyl)-6-fluoro-1-methyl-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
Allyl 2-(1-methyl-2-(5-methylthiophen-2-yl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)benzoate,
3-(2-(2-Methoxyethoxy)phenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one, and
2-(1-Methyl-2-(5-methylthiophen-2-yl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)benzoic acid.
5. The compound of claim 1 , wherein R 4 is a methyl radical.
6. The compound of claim 2 , which is selected from group consisting of
1-Methyl-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-3-phenyl-2-(5-phenylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-3-phenyl-2-(5-(pyridin-2-yl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-2-(5-(methylthio)thiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-([2,2′-Bithiophen]-5-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-(5-(Furan-2-yl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-(5-Ethylthiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-2-(5-(2-methylthiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-(5-Bromothiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-3-phenyl-2-(5-(phenylthio)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
2-(5-(3,4-Dimethoxyphenyl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-2-(5-(3-nitrophenyl)thiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-(5-(Furan-3-yl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
Methyl 4-(5-(1-methyl-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-2-yl)thiophen-2-yl)benzoate,
2-(5-(4-Acetylphenyl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-3-phenyl-2-(5-(3,4,5-trimethoxyphenyl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
1-methyl-2-(5-(4-methyl-3-nitrophenyl)thiophenyl-2-yl)-3-phenyl-2,3-hydroquinazolin-4(1H)-one,
4-(5-(1-Methyl-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-2-yl)thiophen-2-yl)benzonitrile,
5-(1-Methyl-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-2-yl)thiophene-2-carbonitrile,
3-(2-Chlorophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Iodophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Methoxyphenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-3-(2-(methylthio)phenyl)-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Fluorophenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-([1,1′-Biphenyl]-2-yl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
1-Methyl-2-(5-methylthiophen-2-yl)-3-(2-(phenylsulfonyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one,
6-Fluoro-1-methyl-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-(5-(Azidomethyl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-(5-(2-(Azidomethyl)thiazol-4-yl)thiophen-2-yl)-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
2-(5-(2-(Azidomethyl)thiazol-4-yl)thiophen-2-yl)-6-fluoro-1-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Benzoylphenyl)-1-methyl-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
3-(2-Benzoylphenyl)-6-fluoro-1-methyl-2-(5-(2-methylthiazol-4-yl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one,
Allyl 2-(1-methyl-2-(5-methylthiophen-2-yl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)benzoate,
3-(2-(2-Methoxyethoxy)phenyl)-1-methyl-2-(5-methylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one, and
2-(1-Methyl-2-(5-methylthiophen-2-yl)-4-oxo-1,4-dihydroquinazolin-3(2H)-yl)benzoic acid.
7. A method for preventing and/or treating disorders induced by toxins with an intracellular mode of a using retrograde transport, the method comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I):
to a subject in need thereof,
wherein:
R 1 represents a hydrogen atom, a halogen atom or an alkoxy radical having from 1 to 3 carbon atoms;
R 2 is a phenyl ring, optionally substituted with: a phenyl radical, a halogen atom, an —SO 2 -phenyl group or an —S—X or —O—X group, X being an alkyl radical having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms; or a PEG of formula —(CH 2 —CH 2 —O) n —R with n being 1 to 10, and R represents a hydrogen atom or a methyl radical, or a —CO—Y or —CO—O—Y group, Y being a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, a phenyl ring or an allyl (—CH 2 —CH═CH 2 ) group;
R 3 represents a thiophene ring substituted on C5′ of the thiophene, the quinazolinone ring being bonded to C2′ of the thiophene, with
an alkyl radical having from 1 to 3 carbon atoms;
a halogen atom;
a phenyl radical optionally substituted with an alkoxy radical having from 1 to 3 carbon atoms, a —CN group, an —NO 2 group or a —COX or —COOX group with X an alkyl radical having from 1 to 4 carbon atoms, or a combination of these substituents;
an —SY group, Y being an alkyl radical having from 1 to 4 carbon atoms or a phenyl radical;
a —CN group;
a —CH 2 —N 3 group;
an aromatic heterocycle having 5 or 6 atoms selected from the group consisting of a furan, a thiophene, a pyrrole, a pyrroline, a pyrrolidine, a dioxolane, oxazole, a thiazole, an imidazole, an imidazoline, an imidazolidine, a pyrazole, an isoxazole, an isothiazole, a pyran, a pyridine, a piperidine, a dioxane, a morpholine, a pyridazine, a pyrimidine and a pyrazine ring, optionally substituted with at least one alkyl radical having from 1 to 3 carbon atoms, a —CH 2 —N 3 group, or both; and
R 4 represents a hydrogen atom or a methyl radical;
with the exclusion of the compound such that R 1 is a hydrogen atom, R 2 a phenyl radical, R 3 a 5-methylthiophen-2-yl radical and R 4 a hydrogen atom.
8. The method of claim 7 , wherein R 2 is a phenyl ring substituted on its carbon C2″.
9. The method of claim 7 , wherein R 4 is a methyl radical.
10. The method of claim 7 , wherein the toxins with an intracellular mode of action are selected from the group consisting of ricin, Shiga toxin and Shiga-like toxins (Stxs) produced by Shigella dysenteriae (Stx) and E. coli (Stx1 and Stx2), cholera toxin (Ctx from Vibrio cholerae responsible for cholera), pertussis toxin ( Bordetella pertussis , the agent responsible for whooping cough), subtilase cytotoxin and thermolabile enterotoxin ( E. coli ).
11. A pharmaceutical composition or a medicament, comprising at least one compound of formula (I) as defined in claim 1 , in a pharmaceutically acceptable carrier, wherein said pharmaceutical composition or said medicament is adapted to be administered by an airway route, an oral route, a parenteral route or a local route.
12. A pharmaceutical composition or a medicament, comprising at least one compound of 1 formula (I) as defined in claim 7 , in a pharmaceutically acceptable carrier, wherein said pharmaceutical composition or said medicament is adapted to be administered by an airway route, an oral route, a parenteral route or a local route.Cited by (0)
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